1. Field of the Invention
This invention concerns cytosine-containing antibiotic 10381a.sub.1 and antibiotics 10381b, which are obtained by the fermentation of a nutrient medium with a new species of Streptomyces, Streptomyces arginensis. Antibiotics 10381b comprise a group of at least five antibacterial agents active mainly against G-positive organisms and having physical properties similar to those reported for the sulfomycin group of antibiotics.
2. Information Disclosure
Cytosine-containing antibiotics are known in the art. The nucleoside antibiotic gougerotin is disclosed in J. J. Fox et al., Tetrahedron Letters, No. 57, pp. 6029-6032 (1968). The antibiotics amicetin, plicacetin and bamicetin are disclosed in T. H. Haskell et al., J. Amer. Chem. Soc., 80:743-747 (1958). The antibiotics amicetin and bamicetin are also disclosed in C. L. Stevens et al., J. Org. Chem., 31:2822-2828 (1966). The antibiotic blasticidin S is disclosed in H. Yonehara and N. Otake, Tetrahedron Letters, 32:3785-3791 (1966) and in H. Seto and H. Yonehara, The J. of Antibiotics, XXX (11):1022-1024, November 1977.
None of the prior art antibiotics known to Applicant teaches or suggests antibiotic 10381a.sub.1. In addition, there are accordingly unexpected and advantageous properties associated with this new antibiotic 10381a.sub.1, e.g., greatly reduced toxicity.
The production and properties of arginomycin (antibiotic 10381a.sub.1) are described in International Application, PCT/US86/00657 (International Publication Number WO86/05785 dated Oct. 9, 1986), and in A. D. Argoudelis et al., The Journal of Antibiotics, XL (6):750-760, June 1987.
The production and properties of antibiotics 10381b are described in International Application PCT/US87/01450 (International Publication Number WO 88/00200 dated Jan. 14, 1988.
Streptomyces arginensis (Culture 10381) also produces a mixture of solvent-soluble compounds useful as antibiotics against Gram-positive organisms including "resistant" Staphylococcus aureus. These antibiotics have been designated as 10381b antibiotics. The present invention describes the production, isolation and physical and biological properties of antibiotics 10381b.
Chemically, antibiotics 10381b appear to be related to the sulfomycins, which are reported to be peptides of unknown structure. See Y. Egawa et al., "Sulfomycins, A Series of New Sulfur-Containing Antibiotics. I: Isolation, Purification and Properties." J. Antibiotics, 22:12-17 (1969).
As part of an effort to elucidate the relationship between antibiotics 10381b and the sulfomycins, the antibiotic production patterns of S. arginensis and two sulfomycin-producing cultures were compared under the fermentation conditions developed for production of antibiotics 10381b. The three cultures produce activities which appear virtually identical when analyzed by the methods used for antibiotics 10381b. However, only S. arginensis produces antifungal activity (antibiotic 10381a.sub.1 /arginomycin).
Sulfomycins produced by Streptomyces viridochromogenes ss sulfomycini ATCC 29776; UC 8410 were isolated by procedures used for the isolation of the antibiotic 10381b complex. The obtained material was compared to the antibiotic 10381b complex by infrared spectra (IR), ultraviolet spectra (UV), paper chromatography, thin layer chromatography (tlc), high performance liquid chromatography (HPLC) and antibacterial spectra. It appears that antibiotics 10381b are very similar, if not identical, to the sulfomycins. Antibiotic 10381b.sub.2, the main antibiotic, is almost identical to the main activity produced by the sulfomycin-producing organisms, and all indications are that it is Sulfomycin I, which is known in the art, as discussed below. However, the producing organisms are definitely different. S. arginensis (culture 10381) produces arginomycin, while the two sulfomycin-producing cultures do not produce arginomycin or any other antifungal activity.
U.S. Pat. No. 4,007,090 discloses and claims a novel fermentation process for the preparation of sulfomycin from the microorganism Streptomyces cineroviridis.
Sulfomycin I is a known Gram-positive antibiotic described in Japan Pat. No. 45-6880 (Derwent Abstract, Accession Number 18445R). Sulfomycin II and III are also described in the literature as Gram-positive antibiotics in Japan Pat. publication No. 17599/1970 (Derwent Abstract, Accession Number 42550R). All three Sulfomycin antibiotics were prepared by the fermentation of a strain of the microorganism Streptomyces viridochromogenes.